In brain, synaptic connectivity determines which neurons communicate with each other, thereby establishing the wiring diagram of the brain. Changes in synaptic connectivity are probably important in the pathogenesis of a number of mental and neurological diseases, such as AIzheimer's disease and epilepsy. However, the molecular basis for the specificity of neuronal connections is poorly understood. Neurexins are polymorphic, neuron- specific cell surface receptors that may function in specifying cell-cell interactions between neurons. This application describes a genetic approach to elucidate the functions of neurexins in the brain and to test their potential involvement in disease. Three specific aims will be pursued: First, genes encoding murine and human neurexins will be cloned and their exon-intro structure and chromosomal localizations will be determined. This will form the basis for the homologous recombination studies described below and allow the search for candidate diseases in which neurexins may be mutated. Second, the cloned murine genes will be used to delete or selectively mutate endogenous neurexin genes in embryonic stem cells, and mice carrying mutations in different neurexin genes will be generated. Mutant mice with defined deletions or mutations of neurexins will serve as models for functional and pathophysiological studies. Third, mice heterozygous and homozygous for neurexin gene mutations will be analyzed using biochemical, morphological, and physiological techniques to determine the in vivo functions of neurexins and their potential as disease models. Together, these experiments will give insight into the biological functions of neurexins and their potential involvement in mental and neurological diseases.